JPS61267577A - Novel production of dextrorotary optical isomer of ym-09730 diastereomer a - Google Patents

Abstract

(57) [Summary] This bulletin contains application data before electronic filing, so abstract data is not recorded.

Description

Detailed Description of the Invention (Industrial Application Field) The present invention provides a dextrorotatory optical isomer of diastereomer A of YM-09730 useful as a vasodilator and a pharmacologically acceptable acid addition salt thereof. Concerning a new manufacturing method.

(Background of the invention) YM-09730 has a chemical name of 2,6-dimethyl-4-
(m-nitrophenyl)-1,4-dihydropyridine-
Dihydropyridine-3, which is called 3,5-dicarboxylic acid-3-(1-benzylpyrrolidin-3-yl) ester-5-methyl ester and is represented by the following chemical structural formula.
It is a 5-dicarboxylic acid ester derivative.

It has been reported that YM-09730 has a vasodilatory effect and a blood pressure lowering effect, and that these effects are sustained (Japanese Patent No. 1137506, Japanese Patent Publication No. 57-30111).

YM-09730 has two asymmetric carbon atoms,
The existence of isomers based on these asymmetric carbon atoms is presumed from a stereochemical standpoint. However, the existence of this isomer is not described in the above patent publication and is unconfirmed.

The present inventors previously separated diastereomer A and diastereomer B of YM-09730 for the first time, and found that diastereomer A has a unique pharmacological effect that is significantly superior to diastereomer B and a mixture of both diastereomers. (Patent application 1987-75998)
issue).

The inventors further discovered that m-nitrope/dualdehyde and 1-
YM-09730 obtained by a method such as reacting benzyl-3-acetoacetoxypyrrolidine with 3-aminocrotonic acid methyl ester was subjected to column chromatography using silica gel as a carrier and ethyl acetate-acetic acid as an eluent. diastereomer A is separated and then optically resolved using L-(-3-malic acid or the like) to produce a dextrorotatory optical isomer of diastereomer A whose hydrochloride has a melting point of 223 to 230°C. It has been found that the white scale and its isomer have unique pharmacological effects that are much superior to its levorotatory optical isomer and the mixture of both isomers (Japanese Patent Application No. 114098/1982).

(Means for Solving the Problem) As a result of researching this new and useful method for producing the dextrorotary optical isomer of diastereomer A of YM-09730, we found that the yield of the desired isomer was increased.1 The invention has been completed.

Note that diastereomer A itself (dt mixture) has a hydrochloride melting point of 200 to 206°C, and a melting point of 180 to 18°C.
It is distinguished from diastereomer B, which exhibits a temperature of 5°C.

Further, as mentioned above, the dextrorotary optical isomer of diastereomer A has a hydrochloride having a melting point of 223 to 230°C. The present invention provides YM-0973 specified by the melting point.
The present invention provides a novel method for producing a dextrorotary optical isomer of diastereomer-A or a pharmacologically acceptable acid addition salt thereof.

Here, the pharmacologically acceptable acid addition salt is L-(→
-Organic acid salts such as malate and mineral acid salts such as hydrochloride.

Compound (I) of the present invention is a levorotatory optical compound of 5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid represented by formula (n) It can be produced by reacting an isomer or racemate or a reactive derivative thereof with a levorotatory optical isomer or racemate of 1-benzyl-3-hydroxypyrrolidine represented by formula (III).

This reaction is a carboxylic acid ester forming reaction, and commonly used techniques can be used as appropriate.

There is no stereochemical inversion due to this reaction. Compound (n)
Examples of reactive derivatives include acid halides such as acid chlorides and acid bromides, acid anhydrides, mixed acid anhydrides, and active esters. When compound ([1) is used as a free carboxylic acid, the reaction is carried out in the presence of a condensing agent such as dicyclohexylcarbodiimide.

The reaction is advantageously carried out in an organic solvent such as methylene chloride or dimethylformamide under cooling or at room temperature.

When both the starting materials, compound (■) and compound ([1), are levorotatory optical isomers, the product is essentially only the dextrorotatory optical isomer of diastereomer-A.
The target product can be isolated by conventional operations such as extraction and concentration, but column chromatography may also be performed if necessary. In addition, if at least one of the compounds (■) and compound booklet) is a racemate, one reaction solution contains diastereomers in addition to the dextrorotatory optical isomer of diastereomer A of interest.
Since the levorotatory optical isomer of A and the right and levorotatory optical isomers of diastereomer B are included, the target product can be isolated by performing column chromatography and fractional recrystallization in addition to extraction and concentration. can.

For example, a mixture of the dextrorotatory optical isomer of diastereomer A and the levorotatory optical isomer of diastereomer B is subjected to column chromatography using silica gel as a carrier and ethyl acetate-acetic acid as the eluent, and yields YM-09730. to separate the dextrorotary optical isomers of diastereomer-A,
Alternatively, reacting with L-(→-malic acid to obtain L-(→-malate) of the dextrorotary optical isomer of diastereomer A and the levorotatory optical isomer of diastereomer B, and fractionally recrystallizing these. The dextrorotary enantiomer 1.-(→-malate of Yoshidiastereomer-A is obtained.

In separation by column chromatography.

The dextrorotatory optical isomer of diastereomer A can be obtained from the first eluate, and the levorotatory optical isomer of diastereomer B can be obtained from the later eluate.

The silica gel used as a carrier is not particularly limited as long as it is commonly used in column chromatography. There are no particular restrictions on the mixing ratio of the eluent ethyl acetate and acetic acid, but 2 usually ethyl acetate is used as the main component,
It is preferable to mix this with a walking amount of acetic acid.The mixing ratio is approximately 30-50v/v of ethyl acetate to 1-1% of acetic acid.
A value of about 0 v/v is convenient, and as the amount of acetic acid decreases, the elution time of the target compound becomes longer.

Appropriate conditions can be adopted for the elution rate and treatment temperature.

On the other hand, the method using L-(→-malic acid).

The r,-(→-malate salt of the dextrorotary optical isomer of diastereomer-A of YM-09730 is crystalline.

It can also be used to separate its optical isomers by fractional recrystallization. Examples of solvents that can be used in this fractional recrystallization include methanol, ethanol, acetone, and acetonitrile.

The thus obtained L-(→-malate salt of the dextrorotatory optical isomer of diastereomer A) can be used as a medicine as it is, but the acetate salt of the dextrorotary optical isomer of diastereomer A can be used as a medicine. Further, if necessary, the free form can be treated with a base and then treated with a suitable acid to lead to other suitable salts.

(Effects of the Invention) The dextrorotatory optical isomer of diastereomer A of YM-09730 and its pharmacologically acceptable acid addition salts, which are the object compounds of the present invention, are new compounds that have not been described in any literature, and are administered directly into the coronary artery. In terms of the rate of increase in coronary flow rate, the area ratio was approximately 40 times that of the levorotatory optical isomer (body) and 2.5 times that of the isomer combination (64 bodies), and Has high affinity.

According to the production method of the present invention, this new and useful YM-0
The dextrorotary optical isomer of diastereomer-A of 9730 is 1
It can be selectively produced in high yield and has extremely high industrial utility value.

(Example) The present invention will be described in further detail by referring to Examples below. It is recognized that compounds (n) and (III), which are the raw material compounds of the present invention, are known substances, but they are new when applied to the present invention.

Since it could be produced by a useful method, it is shown as a reference example.

Reference Example 1゜(1) 20□t of benzene solution containing 6.04 g of m-nitrobenzaldehyde, 6.32 g of tert-butyl acetoacetate, 0.17 g of piperidine, and 0.6 ml of acetic acid was prepared using an azeotropic dehydrator. Heat under reflux for 6 hours.

Add cold water, add 10 ml of water, and separate the benzene layer.

The benzene layer is saturated with aqueous sodium bicarbonate solution.

After sequentially washing with saturated saline, drying with anhydrous magnesium sulfate. After distilling off the solvent under reduced pressure.

The resulting residue is subjected to silica gel column chromatography. The crystals obtained from the n-hexane:ethyl acetate (5:1 volume ratio) elution were washed with n-hexane, and a mixture of geometric isomers of 2-(m-nitrobenzylidene)acetoacetic acid tart butyl ester was obtained as colorless crystals. 5.82
get g.

Melting point: 33-36°C.

(2) 3.56 g of 2-(m-nitrobenzylidene)acetoacetic acid tert-butyl ester obtained in (1) and 1.41 g of 3-aminocrotonic acid methyl ester were heated under reflux for 20 hours in 7 ml of tert-butanol. .

The solvent was distilled off under reduced pressure, and the resulting oil was treated with n-hexane to obtain the desired 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3,5-dicarboxylic acid. Yellow crystals of 3-tert-butyl ester-5-methyl ester were obtained to obtain 4.6 g.

Melting point: 120-122°C (3) 2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3, obtained in (2) under ice water cooling in 5 tnl of 25% hydrogen bromide acetic acid solution. Add dropwise 5 ml of a toluene solution containing 2.5 g of 5-dicarboxylic acid-3-tert-7" methyl ester. Stir for 5 minutes under cooling with ice water, then pour into 50 ml of ice water. Using 10% sodium hydroxide. The aqueous layer is acidified with concentrated hydrochloric acid and the precipitated crystals are collected. The crystals are washed with ether to obtain the desired 5-methoxycarbonyl-2,6-dimethyl- 4-(m
-nitrophenyl)-1,4-dihydropyridine-3-
1.24 g of carboxylic acid (racemate) is obtained.

Melting point: 203-204°C (decomposition) Reference example 2: 25 ml of a solution of 7.55 g of m-nitrobenzaldehyde, 5.75 g of 3-aminocrotonic acid methyl ester, and 7.90 g of tert-butyl acetoacetate in tert-butanol was added to 22 Heat to reflux for an hour. The solvent is distilled off under reduced pressure, and the resulting residue is dissolved in 150 ml of toluene, washed successively with 10% hydrochloric acid, saturated sodium bicarbonate solution and saturated brine, and then dried over anhydrous magnesium sulfate. The solvent was distilled off under reduced pressure to obtain 19.62 g of an oily substance. Dissolve this in 20 m7 of toluene and cool with ice water for 2
Add dropwise to 20 ml of 5% hydrogen bromide and acetic acid solution. 5 at the same temperature
After stirring for a minute, pour into 200 ml of ice water. Add 250 mt of 10% sodium hydroxide to make it basic, and then wash with 100 ml of toluene. The aqueous layer is made acidic with concentrated hydrochloric acid, and the precipitated crystals are collected to obtain the desired 5-methoxycarbonyl-2,6-dimethyl-4-(m-nitrophenyl)-1,4-dihydropyridine-3-carbonyl. 4.51 g of acid (racemate) is obtained. The optically active substance is Chemical and Pharmaceutical Brech, 7 (C
hem.

Pharm, Bull, ), 38, 2809
(1980).

Reference Example 3゜(1) dt -1-benzyl-3-hydroxypyrrolidine 17.7 g,! :D-(→-mandelic acid 15.2
g was heated and dissolved in 66 m7 of acetone, left to stand overnight at 4°C, and 8.5 g of precipitated crystals were recrystallized from 26 mt of acetone to obtain (S)-(→D-( of -1-benzyl-3-hydroxypyrrolidine). → Obtain 5.1 g of mandelate.

Specific optical rotation [α1g −45,5° (C=1.methanol).

Even after repeated recrystallization, there was no change in the specific rotation.

Melting point: 101-102°C. The (S) unitary salt N obtained here
-CH2-Ph nuclear magnetic resonance spectrum) / shi is 4.03
ppm (Singlet, 2H) K observed, (R) quartet of type AB at 4.01 ppm (J = 1
2.5 Hz) was not observed.

(2) Dissolve 22 g of (S)-(→-1-benzyl-3-hydroxypyrrolidine D-(→-mandelate) in 50+nl of chloroform, and wash the chloroform layer with a solution of 14.4 g of anhydrous sodium carbonate in 90 ml of water. The mixture was dried over anhydrous magnesium sulfate, chloroform was distilled off, and then distilled under reduced pressure to obtain (S) -(→-1-benzyl-3-hydroxypyrrolidine x 1.sg. Boiling point 109°C/
0.65 mmHg, [α] -3.77° (c
= 5, methanol).

Reference example 4゜(S) -(→-75g of malic acid was mixed with 75g of benzylamine
React with m1 at 170 °C for 3 hours (S)-(-)-1
-benzyl-3-hydroxycoba, phosphoric acid imide 5.27
I got g.

Melting point 99-101°C; [α B-s1.1° (C=1
゜methanol).

9.73 g of lithium aluminum hydride was suspended in 340 rnl of anhydrous tetrahydrofuran, and the imide 2 was suspended in 200 ml of anhydrous tetrahydrofuran under water cooling.
0.5 g was added dropwise. After heating under reflux for 3 hours.

After cooling, 100 g of sodium sulfate decahydrate was added thereto. Stir overnight under water cooling, remove insoluble materials, concentrate solution F under reduced pressure, and distill the residue under reduced pressure.
115°C/08 mmHg=[α]B 3.0
13.8 g of (S)-(→-1-benzyl-3-hydroxypyrrolidine) was obtained.

The (S)-(→ body obtained in this way was determined from the nuclear magnetic resonance spectrum of the hydrogen at the 3-position with the addition of a shift reagent [Eu-TFMC(III)], indicating that 10% of the R-((1) body) was This (S) -8 isomer was converted to D-(→ mandelate salt as in Reference Example 3) and recrystallized from 3 volumes of ethanol and then 6 volumes of ethanol-toluene (1:5). The obtained mandelate [[α]; −45,2° was treated.

(S)-H-1-benzyl-3-hydroxypyrrolidine [boiling point 115-120°C/1.2-1.5 mmHg
, 8.6 g of [αcoB -3,77° (C=S, methanol) is obtained.

Reference Example 5 3.4 g of 2-(-)-pinene was added to 50 mt of 9-borabicyclo[3,3,1]nonane (0.5M solution in tetrahydrofuran) and stirred at 60°C for 5 hours. Cool to room temperature, ■-benzyru-3-pyro! J shi/y 1.75
Add g. After stirring for 4 days at room temperature, 1.3 ml of acetaldehyde is added at 0°C. The solvent was removed under reduced pressure.

Add 20 ml of ether to the residue. Cool to 0°C.

Add 1.5 ml of 2-amine ethanol and stir. Sweep away the formed precipitate. The ether solution is extracted with IN-hydrochloric acid, the hydrochloric acid layer is made alkaline with sodium carbonate and extracted with dichloromethane. The extract was dried over anhydrous magnesium sulfate and concentrated to obtain 1.1 g of a crude product. The crude product was distilled under reduced pressure to obtain 0.6 g of purified product. Boiling point 106℃/0.
9 mmHg0 (S)-H-1-benzyl- obtained here
3-Hydroxypyrrolidine is a shift reagent [Eu-TF
From the nuclear magnetic resonance spectrum of hydrogen at the 3-position with addition of MC(ill)], it was found to be 30% 0% enantioeffes, e,).

Example 1 5-methoxycarbonyl-26-dimethyl-4-(m-
(nitrophenyl) -1,4-cyhydrohyridine-3-
Carboxylic acid 33211! Dissolve g in 3 ml of dichloromethane and add 250 ff of phosphorus pentachloride while stirring while cooling with ice water.
1 g of the mixture was added, and the mixture was further stirred at the same temperature for 1 hour.

The reaction solution was cooled to -30°C, and (s)-1-benzyl-3
- Add 177 fftg of hydroxypyrrolidine, -30
After reacting at ℃ for 2 hours, the mixture is washed with water and saturated aqueous sodium bicarbonate solution, and the solvent is distilled off to obtain an oily substance. The oil was subjected to silica gel column chromatography, eluted with ethyl acetate-acetic acid (5:1 v/v), and then subjected to high performance liquid chromatography [Column: Nucleosil 5 C+s
4.6mm x 300mm.

Column temperature = 30°C, mobile phase: 0.05 mol of tetra n-pentylammonium bromide (3 mM) + potassium dihydrogen Jy acid (pH 3) - acetonitrile (
80:20v/v), flow rate: 0.9ml per minute, YM-0 showing a retention time of 28 minutes with ultraviolet detection (λ254nm).
The dextrorotary optical isomer of diastereomer-A of 9730 was obtained. This is treated with saturated sodium bicarbonate in chloroform and then dilute hydrochloric acid to yield the hydrochloride salt of the dextrorotary enantiomer of YM-09730 to the diastereomer, 1611TIg.

Melting point 228-230°C (decomposed) Specific rotation [α] +116.3 (C=0.5.methanol).

Example 2゜(-)-5-methoxycarbonyl-2,6-dimethyl-
332 mg of 4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was dissolved in dichloromethane 3
ml of phosphorus pentachloride while stirring under water cooling.
1 g of the mixture was added, and the mixture was further stirred at the same temperature for 1 hour. The reaction solution was cooled to -30°C, and 177 ff1g of (S)-1-benzyl-3-hydroxypyrrolidine was added.

After reacting for 2 hours at =30°C, the reaction mixture is diluted with 5 ml of dichloromethane and washed twice with 5 ml of water and then twice with 5 ml of saturated sodium bicarbonate solution. The oil obtained by concentrating the solvent under reduced pressure was subjected to column chromatography using silica gel (15 g), and toluene-ethyl acetate (4
:1v/v) and concentrate the fraction containing the target product. Dissolve the residue in 5 ml of chloroform and
．． Add 1 ml of 8N hydrochloric acid-ethanol solution and concentrate the resulting solution again under reduced pressure.

The residue was dissolved in 2 m4 of methanol, left to stand overnight under water cooling, and the precipitated crystals were filtered and dried to yield YM-09730.
Hydrochloride salt of the dextrorotary optical isomer of diastereomer-A 35
Obtain 0 mg.

Melting point 226-228°C (decomposed) Specific rotation [α]. +116.4° (c=1.methanol) nuclear magnetic resonance spectrum (CD30D, TMS internal standard, δppm) 1.80-2.70 (2H, br
oad m, C4'-H2)2.32.2.34
(6H, s, C2, a-CHl) 3.0-4.0
(4H, m, C2',!'-H2) 3.64
(3H,s, -COOCH3)4.42
(2H,s,-CHzl)5.08
(LH,s, C4-H)5.30 (I H
, m, C3'-H) 7.30-8.20 (9H
, m, H of benzene ring) Example 3゜(-)-5-methoxycarbonyl-2,6-dimethyl-
8401r1g of 4-(m-nitrophenyl)-1,4-dihydropyridine-3-carboxylic acid was dissolved in a mixed solvent of dichloromethane, N,,N-dimethylformamide (4:1
y/v) to 6 ml, add 0.2 ml of thionyl chloride under water cooling, and stir under water cooling for 1 hour. A solution of 450 mg of di(S)-1-hensyl-3·-hydroxypyrrolidine and 3 rnt of dichloromethane in the resulting reaction solution was added dropwise under water cooling, and the mixture was further stirred under water cooling for 15 hours. The reaction solution was diluted with 10 ml of dichloromethane, and washed sequentially with 10 ml of water, 10 ml of a saturated aqueous solution of sodium bicarbonate (twice), and 10 ml of saturated brine. The dichloromethane layer was dried over anhydrous magnesium sulfate, concentrated under reduced pressure, and the resulting oil was subjected to column chromatography on silica gel (40 g), toluene-ethyl acetate (initially 4:1 v/
v, then eluted with 1:l v/v).

Concentrate the fraction containing the target product. Concentrated oil (990mg
) in 10 ml of chloroform, add 2.6 ml of 0.8N hydrochloric acid-ethanol solution, and concentrate the resulting solution again under reduced pressure. The residue was dissolved in 5 ml of methanol, left to stand overnight under water cooling, and crystals precipitated by filtration and drying to obtain 850 mg of hydrochloride of the dextrorotatory optical isomer of diastereomer-A of YM-09730.

Melting point: 226-228°C (decomposed) Specific rotation: [α]D+116.4° (c = 1, methanol) Nuclear magnetic resonance spectrum (consistent with the compound obtained in Example 2) Example 4
゜1) Concentrated oil obtained in the same manner as in Example 3 (990
ml) in 10 ml of ethanol, and concentrated again under reduced pressure. To the residue, add 5 ml of ethanol and dissolve. The solution was allowed to stand overnight under water cooling, and the precipitated crystals were filtered and dried to obtain 730 mg of the free base of the dextrorotatory optical isomer of diastereomer A of YM-09730.

Melting point 137-139°C Specific rotation [α] +64.8° (e=1.methanol) nuclear magnetic resonance spectrum (CDCl3. TMS internal standard, δppm) 1.40-3.0 (6H, m, C2
',4',,'-H2)2.34.2.36 (6
H,s, C2,6-CH3)3.65 (5H,s
, -COOCHL and -c■2o)5.10 (I H
,s, C4-H)5.12 (I H,m, C8
'-H) 5.78 (I H, broad a,
NH)7.1-6~8.24 (9H,m, H of benzene ring)2) Diastereomer-A of YM~09730
700 mg of the free base of the dextrorotatory enantiomer of was added to 10 ml of chloroform and 1.8 mL of 0.8N hydrochloric acid-ethanol solution.
ml and concentrate under reduced pressure. The obtained oil was dissolved in 3.5 ml of methanol and left to stand overnight in a trap under ice cooling to obtain a crystalline filtration. After drying, the dextrorotary optical isomer of diastereomer A of YM-09730 was dissolved in hydrochloric acid. Obtain 630 μ of salt.

Melting point 228-230°C (decomposed) Specific rotation [α] +116.7° (c=1.methanol) Nuclear magnetic resonance spectrum (consistent with the compound obtained in Example 2) Shozo Nagai 1, Incident display Patent Application No. 12358 of 1985 2 New method for producing the dextrorotary optical isomer of diastereomer-A of YM-09730 Title 3 Relationship to the case of the person making the amendment Patent applicant address 2 Nihonbashi Honmachi, Chuo-ku, Tokyo Chome 5-1 name
(667) Yamanouchi Yakuhin Co., Ltd. Representative: Shigeru Morioka 4, Agent address: 1-8-5, Azuzawa 1-chome, Itabashi-ku, Tokyo, Date of amendment order - March 19, 1985 (shipment date: s, 61.3.25)
6. Documents and specifications certifying the power of attorney subject to amendment 7. Contents of amendment (11) Submit a power of attorney and a translation of the power of attorney as shown in Attachment 11.

(2) Submit an engraving of the specification (with no changes to the contents) as shown in the attached sheet.

Claims (1)

[Claims] The hydrochloride has a melting point of 223 to 230°C (decomposition) (±)
-2,6-dimethyl-4-(m-nitrophenyl)-1
,4-dihydropyridine-3,5-dicarboxylic acid 3-
(1-benzylpyrrolidin-3-yl)ester 5-
When producing the dextrorotary optical isomer (I) of diastereomer A of methyl ester or its pharmaceutically usable acid addition salt, the formula (A) ▲ There are mathematical formulas, chemical formulas, tables, etc. ▼ (II) The dextrorotatory optical isomer of the compound represented by the formula ▲Mathematical formula, chemical formula, table, etc.▼(III) is reacted with the dextrorotatory optical isomer of the compound shown in (I) or
or (b) reacting compound (II), at least one of which is racemic, with compound (III), and obtaining the above-mentioned dextrorotatory optical isomer (I) from the reaction product by column chromatography or fractional crystallization. How to characterize it.